Evaluation of treatments that modify the progression of COPD have been limited by the requirement for large numbers of participants and long follow-up intervals to establish efficacy. The traditional outcomes to document progression of COPD have been decline of lung function or mortality. Animal models of emphysema and COPD have been useful to dissect pathwaysfor COPD pathogenesis, but have not been developed as platforms for testing potential disease-modifying agents. In this project, we plan to test two promising treatments that may modify the progression of COPD: azithromycin, an immunomodulatory macrolide antibiotic, and losartan, an angiotensin receptor blocker. Preliminary evidence in humans and animals shows that these two drugs are effective in blocking pathways important in the progression of COPD. W plan to conduct a three-group placebo-controlled proof-of-concept clinical trial in 180 people with COPD assigned to azithromycin 250 mg thrice weekly., losartan 50 mg daily, or placebo. The primary outcome measures are indicators of anatomic lung remodeling [unreadable]quantitative measures of emphysema and airway wall dimensions by HRCT. Secondary outcomes will be a panel of biomarkers of systemic and respiratory inflammation and oxidative stress. Clinically relevant outcomes will include lung function and respiratory symptoms. Novel outcomes include measurement of airspace dimension using hyperpolarized helium MR imaging, and measures of innate immune responsivity of alveolar lavage cells. Concurrently, we will test these treatments using parallel outcomes in two strains of susceptible cigarette-smoke exposed mice to further understand which molecular pathways are involved. In particular, we will focus on the role of TGF-beta as a central regulator of lung remodeling in smoke-exposed mice. Measurements of disease progression will be made by histologic morphometry and hyper-polarized helium MRI. Other outcome measures include lung and systemic activity of cytokines, chemokines, growth factors, indicators of oxidative stress and apoptosis. Studies will be done to determine if these candidate drugs are effective in reducing progression of disease if given concurrently with smoking, or are effective after smoking injury has occurred and exposure has ceased.. The overall goal of this project is to provide information on the validity, reliability, and utility of intermediate endpoints and biomarkers in COPD clinical research and the value of animal models for testing treatments that can modify the progression of COPD.